Technical Field
The present disclosure provides compositions and methods for treating or reducing the risk of pancreatic cancer and, more specifically, compounds capable of inhibiting the expression or activity of RUNX3 that are useful in minimizing or eliminating the metastasis of pancreatic cancer.
Description of the Related Art
Patients with carcinomas die of metastatic disease. Rarely do they succumb because of the primary tumor alone. This is especially true of pancreatic ductal adenocarcinoma or, more commonly, pancreas cancer. Pancreas cancers appear to calibrate the often competing needs of local growth and distant spread to generate a profoundly lethal disease. While early metastasis characterizes the majority of clinical presentations, extension of locally invasive disease in others not only precludes surgical resection, but can also lead to demise.
Pancreatic ductal adenocarcinomas (PDAs) are thought to initiate most commonly in precursor lesions, termed pancreatic intraepithelial neoplasias (PanINs), which arise in the terminal ductules (Hruban et al., Am. J. Surg. Pathol. 25:579, 2001). Activating mutations in the KRAS proto-oncogene occur early in preinvasive disease and are almost uniformly present (>90%) in invasive PDA. Mutations in CDKN2A/INK4A are similarly abundant in invasive disease (>95%) and point mutations in TP53 are also extremely common (>75%). Mutations in DPC4/SMAD4, the last of the cardinal genetic events associated with PDA, occur late in the PanIN-to-PDA progression scheme and are ultimately found in approximately 50% of invasive cancers (Hruban et al., Clin. Cancer Res. 6:2969, 2000).
Ductal adenocarcinomas of the pancreas can also arise from two clinically, histologically, and genetically distinct classes of macroscopic cystic precursors, intraductal papillary mucinous neoplasms (IPMN) and mucinous cystic neoplasms (MCN) (Hruban et al., Gastroenterology Clinics of North America 36:831, 2007). Interestingly, although both MCNs and IPMNs can culminate in invasive PDA, the carcinomas that arise from these cystic routes portend significantly better prognoses for patients than the classical route (Hingorani, Gastroenterology 133:345, 2007; Hruban, 2007; Poultsides et al., Ann. Surg. 251:470, 2010).
Pancreatic cancer is an unusually lethal disease with the highest 1-year and 5-year mortality rates of any cancer. Notoriously difficult to detect and resistant to all current therapeutic modalities, PDA has already advanced locally or frankly metastasized in most patients at the time of diagnosis; median survival in this setting is approximately 6 months (Hidalgo, New England J. Med. 362:1605, 2010). For the fortunate few for whom surgical resection is possible, median survival increases to 2 years but is not durable: survival at 5 years is only 20% and continues to decline to less than 2% at 10 years (Allison et al., J. Surg. Oncol. 67:151, 1998). The majority of these resected patients also eventually die of metastatic disease, which indicates that clinical Stage I tumors are, in fact, already micrometastatic Stage IV. In this regard, PDA is unlike any other major epithelial malignancy, or solid tumor for that matter, in which chronologically distinct stages of disease permit meaningful surgical interventions that can prolong survival and even effect cures.
Hence, there remains a need in the art for alternative therapies and methods for reducing the risk of or treating pancreatic cancer and associated disorders. The present disclosure meets such needs, and further provides other related advantages.